Substituted pteridines and method



Patented June 2t), 1950 SUBSTITUTED PTERIDINES AND METHOD OF PREPARING SAME James M. Smith, Jr., North Plainfield, and Donna B. Cosulich, Bound Brook, vN. J., assignors to American Cyanamid Company,

New York,

N. Y., a corporation of Maine No Drawing. Application October 22,l1947, .Serial No. 781,492

15 Claims. 1

This invention relates to new organic com pounds and to processes of preparing the same.

Recently pteroic acid and some of its amino acid amides have been synthesized and found to possess biological activity. Some of these, particularly theglutamic acid amides of pteroic acid, such as N-[4-{--[ (z-.amino--hydroxy-G-pyrimido [4,5-bJ Py azyl) methyl] amino}benzoyl] glutamic acid, have been-found effective in stimulat- -nigthe formation ofthemoglobin and useful in the treatment of macrocytic anemia, sprue-and other diseases. This latter compound is also commonly known as .folic acid and is now Widely employed in medicine. A process of preparing such compounds is described in the copending ap- ,plication of Coy W. Waller and John H. Mowat, Serial Number 606,704, filed July 23, 1945,, now

- Patent Number 2,500,296.

We have found that certain vicinal diamino {pyrimidines may be reacted with an alpha, betadi halopropiorlaldehyde and secondary amines of the type to be described hereinafter to yield new compounds. Although some of these are related to .folic acid structurally, they-possess entirely different physiological activity. Most of the new compounds of the :present invention antagonize folio acid in the animal body and, accordingly, are "of very great potential importancein medicine in an experimental capacity .and possimy :in the treatment of disease. The new :pterins "12 zone, carbon tetrachloride, chloroform, acetic acid and other organic liquids and mixtures thereof with each other or-wa-ter. Some reaction may take place, however, by merely mixing the necessary reactants together and heatingthe mixture.

v The reaction may take place over a wide'rang e of temperatures of from-about 0 Cs up. to about 100 C. or even higher. .Likewise, the reaction 10" will take placehover a wide range of pH conditions, best results being obtained on the-acid side .ata pH within the range of about 1.5.1706.

,As noted above, the reaction may .be caused to take place by mixing..a.ll.three of the intermediates simultaneously and after reaction thereof recovering theresultingproduct. It may be .desir-able, however, in some cases to first react the 4,5-diaminopyrimidine with the dihalopropionaldehyde before adding the secondary ..aromatic amine to the-reaction mixture or, ionrthe other hand, to first react the secondary aromatic amine. with the dihalopropionaldehyde and then react the mixture with the yicinal diami-ne.

The 4,5-diaminopyrimidines may be added .to

the reaction mixture in the formof the freebase or as one of the .acid salts which are usually more readily available and easier to handle. than. the

free base. .Itshouldbenoted,however,.thatinsoof the present invention and the ,process by which they may be prepared are shown by the equation which follows. In the general formulae X and Y are hydrogen, hydroxy, sulfhydryl, alkyl, rhalo, amino -:or other radicals, R .isan 'a'lkyl or substituted allml radical, and R isan aromatic TC'HzN I I v A Thereaction may beimade to take place by si multaneously the three intermediates to- .gether, preferably in the presence of water which :serves as solvent Jforfthe intermediates and/or the reaction product.- Suitable solvents iorjthe far as the reactionis concerned the .efiective reactant probably :the ionized .form .of. the diamine. Tautomeric forms .of some of the diamines are possible, .and such arenot excluded from the scope ofthe present invention.

' The preparation .ofmany of the 4,5-yicinaldiaminopyrimidines contemplated .as intermediates .in the process .of the .present invention has been described in the literature. These may 'becmafde .by various processes including .(l) nitrosating a suitable 4-.aminopyr imidine and thereafter reducing the .nitroso group to obtain the correspondin 4,5-diam'inopyrimidine; ('2') coupling a 'diazoniumsalt with a suitable 4.-aminopyrimidine .and thereafter reducing the azo group toan amino radical; and. (3) nitrating a 4-aminopyrimidine having desired substituents .on the 2 I .and/or 5 positions and thereafter reducing the .nitro .group. "By such reactions. T4,'5--?dlaminopyrimidines-can The prepared having a variety .oftdifieren't types. and kinds of radicals on" the land/or '6 positions on the pyrimidine ring. "Such radicals include the amino, hydroxy, sulfhydryl,

alkyl, halo and others. Representative examples of theuse of such pyrimidines areillustra'ted hereinafter. reaction also includ ethyl .a1cohol,;acetone, henmid 'Ihejdihaloprup'ionaldehydes that may'beusied fused aromatic pyrimido-pyrazyl nucleus. oxidation of the non-aromatic dihydro pyrimidonone- 2.

substituted alkyl radicals such as benzyl, 1

-CI-I2COOH, and the saltsand-esters thereof, phenacyl and others. Most of these are represented in the specific examples which ,follow.

The preferred aromatic radicals represented by the group R include benzoic acid and its salts, esters and amides. Particularly useful are the amides of amino acids such as glutamic, aspartic, glycine, leucine, 'serine, phenylalanine, cysteine, isovaline and others. *Amides of amino acids having a peptide linkage such as glutamylglutamic acid and glutamylglutamylglutamic acid are also inc1uded'within the scope of the present invention. The amino acid portion of the radical represented by R maybe natural or synthetic and may be in any of the d. l, or d,l forms. Free carboxyl groups of these amides may be esterified or neutralized or converted into an amide without interfering with the essential reaction. The use of secondary amines in which the group R represents a benzoic acid amide of amino acid is shown in several of the specific examples. Obviously, others may be employed in the same reaction without material modification of the conditions of the reaction; Although the reaction is not greatly affected by the'natureof the group R the biological activity of the resulting products is radically affected by the substituent.

- It might be expected upon consideration of the reactants used in the process that the final product would be a dihydropterin. As shown, howj ever, the resulting product has two less hydrogen atoms than expected, the product having a The pyrazyl nucleus to -the "aromatic form occurs by some obscure mechanism such as internal oxidation or dispropor'tionation in'that the aromatic form is obtained even under nitrogen. Better results are obtained in theprocess'however, when oxidizing agents are added to'thereaction mixture; Suitable oxidation-agents are those having 'f an oxidation-reductionpotential of about-0.49 to 1.42 volts. Among these may be mentioned "iodine, potassium bromate, chlorine, benzoquinone, manganese dioxide, sodium 'dichromate,

ferric chloride, and still'othe'rs. The use of some of these is illustrated in the specific examples.

' The new compounds 'Ofthe present invention may also be prepared by a process analogous to that described in the co-pending application of f Martin E. Hultquist'and Paul F. Drei sbach, Serial No. 701,082, filed October"4,'1946, now Patent" Number 2,443,165' In this modification which is fillustrated in some of thespecific examples 2,4,5 ,6- 'tetraaminopyrimidine is reacted with a secondary aromatic amine and a 1,1-dihalo-3-halopropa- In general," the conditions described" ltherein'may be usedQto prepare the new compounds of the present invention. I

The process and representative'compounds of .the invention will now be disclosed in detail in the following examples. It will be understood, of

unless-otherwise indicated. Example I 21.4 grams (0.0834 mol) 2,4,5-triamino-6-hydroxypyrimidine sulfate monohydrate and 20.4 grams (0.0834 mol) barium chloride dihydrate are slurried in 58500. water at 60 C. for 10 minutes. After cooling to 40 C., 12.6 grams (0.034 mol) p-methylaminobenzoic acid are added, and the pH of the mixture adjusted to 3-4. Simultaneously 36.6 grams (0.083 mol) of a solution of 2,3-dibromopropionaldehyde in acetic acid, a solution of 10.4 grams (0.0417 mol) iodine and 20.8 grams potassium iodide in 67 cc. water, and 50% caustic are added over a 30 minute period. The mixture is kept at 40 C. and pH 3-4. The crude material isisolated by filtration with-a filter aid, such as Hyfio. This crude material reverses the biological activity of pteroylglutamic acid.

'To purify the crude product obtained-above 12.6 grams of the crude 4-[N-(2-amino-4-hydroxypyrimido [4,5-b] pyrazyl-G-methyl) N- methylaminol'ben'zoic acid, 9 grams lime, and 1750 cc. water 'are heated at 60 C. for 40 minutes. After addition of 25 grams Hyflo; the mixture is filtered and the cake washed with 750 cc. water at 60 C. To the filtrate is added 25 grams Hyflo and a 10% solution of zinc chloride'to pH 10 to 11. The solids'are filtered oiiandto the filtrate at C. are added 25 grams Hyfio and a 20% zinc chloride solution to pH- 6.99.' The zinc salt is isolated by filtration, dissolved in 2-500 cciwater containing caustic at 80 C. and reprecipitated by addition of 20% zinc chloride topI-I 6.99; This zinc salt reprecipitation was repeated '3 times The final zinc salt cake is slurried in 875 cc. water containing 1.5 grams lime. After heating at 60 C. for 40 minutes the solids are removed by filtration and washed with 375cc. water. The filtrate is treated with 25 grams-I-Iyflo and 10% zinc chloride solution-to pH 9.82. The filtered solution is added slowly to cc. 30% acetic acid at 80 C. The yellow micro-crystalline material isolatedis80%pure5 W Example II,v

A mixture of 3.85 grams 2,4,5-tri amino-6-hydroxypyrimidine sulfate monohydrate and 3.66 grams barium chloride dihydrate in 70 cc. water was heated to 60 C. for 10 minutes. After'cooling to 40 C. 0.825 gram p-ethylaminobenzoic acid is added and the pH adjusted to 3-4. Keeping the mixture at 40 C. 3 cc. of a solution of 2,3-dibromopropionaldehyde in acetic acid is added simultaneously with a solution of 6.25 grams iodine and 12.5 grams potassium iodide in 40 cc. water and with 50% caustic to maintain pH 3-4. The crude material is isolated with a filter aid. It shows antagonist activity against pteroylglutamic acid. Further purification may be brought about by the procedure described in Example I.

Example III Y Y I A mixture r 251? grams 2.415 mani ine45-mdroxypyrimidine'sulfate monohydr'ate, 24.4 grams barium chlorideydihydrate,and 700cc. of water ingto 40 0., 19.3 grams ofp-butylami'nobenzoic acetic acid at 80 C.

aaisgwa acid is added, and the pH of the mixture adjusted Q-.3T. At 40 C. simul ane usly a d a tagonist activity against pteroylglutamic acid.

Example IV 4-[N-(2-amino-4 hydroxypyrimido [4,5-b] pyrazyl-fi-methyl) -N-benzylaminol benzoic acid is prepared as in Example III above except that 22.7 grams of p-benzylaminohenzoic acid is used instead of the hutyl compound.

Example V 4-[N-(2,4-dihydroxypyrimido [4,5-b] pyrazyl- .(i-rnethyl) -N-methyl'aminol benzoylglutamic acid is; prepared as described in Example III except that 14.2 grams 2,4-dihydroxy-5,6-diaminopyrimidine is used in place of the triaminopyrimidine.

Example VI 1.65 grams 2,4,5-triamino-6=-hydroxypyrimidine suliate, 1.58 grams barium chloride dihydrate and 70 cc. water are heated to 60 C. for minutes and cooled to 40 'C. 1.275 grams p-phenacylaminobenzoic acid are added and the pH adjusted to. 3-4. At 40 C. are added simultaneously solutions of iodine in potassium iodide, 2,3-dibromopropionaldehyde, and caustic to maintain pHv 3-4. The crude 4-[N-(2-amino 4 hydroxypyrimido [45-h] pyrazyl-o-methyl) N phenacylamino] henzoic acid which is isolated shows antagonist activity against pteroylglutamic acid.

Example VII A mixture of 25.7 grams 2,4,5-triamino-6-hydroxypyrimidine sulfate monohydrate, 24.4 grams barium chloride dihydrate, and 700 cc. water are heated to 60 C. for 10 minutes. After cooling to 40 C. 32.4 grams disodium-p-methylaminobenzoylglutamic acid is added and the mixture adjusted to pH 3-4. Simultaneously and at 40 C. solutions of 21.6 grams of 2,3-dibromopropionaldehyde in acetic acid, 12.5 grams iodine and 25 grams potassium iodide in 100 cc. water, and

caustic to maintain pH 3-4 are added. The crude 4-LN-(2-amino 4 hydroxypyrimido [4,5-b] pyraayl-G-methyl) N methylamino] benzoylglutamic acid which is isolated has antagonist activity against pteroylglutamic acid.

One-half of the crude material prepared above is heated with 2 liters water and 9 grams lime to 60 C. for 40 minutes. After adding 25 grams I-Iyfio, filtering, and washing, the filtrate is treated with 25 grams Hyflo and a solution of 10% zinc chloride to pH 10.99 and filtered. The filtrate is heated to 80 C. and zinc chloride solution added to pH 6.9. After filtering with grams Hyiio, the cake is treated with 3 liters water and caustic to pH 11-12 at 80 C. for 10 minutes. At 80 C. 20% Zinc chloride solution is added to pH 6.9. The zinc salt is filtered off hot and reprecipitated 6 times more as described.

The last zinc cake is treated with 1 liter water and 5 grams lime at 60 C. for minutes. After filtering and washing the cake, 20 grams I-Iyfio and 10% zinc chloride solution are addedto pH 10.81. The filtrate is added to 100 cc. of 30% The solid obtained on 0091- i ing is filtered-with 12.5 grams'Hyfio. Thewashed cake istreated-with 1 liter of water, 0.6 gram magnesiumoxide and 1 gramcharcoal at C.

for /2 hour. The hot filtrate is added to cc. of 30% acetic-acid. On cooling, the purified material was obtained. This showed antagonist activity against pteroylglutamic acid. l

' Example VIII 4-,[N-.(2 -.a mino..-. 4 hydroxypyrimido [4,5-bl pyrazyl-G-methyl)-Nephenacylaminol benaoylglutamic acid is prepared as described, in Example II except that 1.925 grams p-phena-cylaminobenzoylglutamic acid is used instead of p-eth laminobenzoic acid. The crude material isolated shows. antagonist activity against pteroylglutamic acid.

Example IX A slurry of 1219 grams 2,4,5-triamino-6-hydroxypyrimidine sulfate monohydrate and 12.2 grams bariumchloride dihydrate in 350 cc. Water is heated to 60 C. for 10 minutes, treated with 7.6 grams N-methylanthranilic acid, cooled to 40 C., and adjusted to pH 3-4. Then is begun the simultaneous addition of 5.4 grams dibromopropionaldehyde in 5.4 grams acetic acid, 6.25 grams iodine and 12.5 grams potassium iodide in 40 cc. water, and 5 N sodium hydroxide to maintain pH 3-4. After stirring 10 minutes and cooling to 20 C. the crude 2-[N-(2eamino-4hydroxypyrimido- [4,5-blpyrazyl-6-methyl) -N-methylaminol benzoir'. :acid is isolated by filtration.

Example X A slurry of 2.9 grams 2,4,5,6-tetraaminopyrimidine sulfate dihydrate and 2.4 grams barium chloride dihydrate in 70 cc. water is heated at 60 C. for 10 minutes, treated with 1.5 grams 4-methylaminobenzoic acid, cooled to 40 C., and adjusted to pH 3-4. Then over a 20 minute period are added simultaneously 2.16 grams dibromopropionaldehyde in 2.16 grams acetic acid, 1.25 grams iodine and 2.5 grams potassium iodide in 8 cc. water, and 5 N sodium hydroxide to maintain pH 3-4. After stirring 10 more minutes and cooling to 20 C., the crude 4-[N-(2,4-diaminopyrimido [4,5-b] pyrazyl-G-methyl)-N-methylamino] benzoic acid, isolated by filtration, is an antagonist to pteroylglutamic acid.

The above product is purified as in Example I except that the purification is run at twice the concentration because of the increased solubility of this compound. The antagonist properties are increased on purification.

Example XI A slurry of 22.3 grams 4,5,6-triaminopyrimidine sulfate and24.4 grams barium chloride dihydrate in 700 cc. water is heated at 60 C. for 10 minutes, treated with 15 grams p-methylaminobenzoic acid, cooled to 40 C., and adjusted to pH 3-4. Then over a 20 minute period are added simultaneously 21.6 grams dibromopropionaldehyde in 21.6 grams acetic acid, 12.5 grams iodine and 25- grams potassium iodide in 80 cc. water, and 5 N sodium hydroxide to maintain pH 3-4. After stirring. 10 minutes more and cooling to 20 C., thecrude 4-[N-(4-aminopyrimido. [4,5-b] pyrazyl-6-methyl) -N-.methylamino] benzoic acid is isolated byfiltration.

Example XII A mixture of 1 2.25grams, of ethyl chloro-acetate and 33 grams ofdhenzocaine; is heated at to for 5.110. 6. hours. On, cooling, the mix-=- of N caustic soda.

chloric acid. Evaporation of the washed and dried ether layer yields the crude ethyl-N-[4- ethoxyphenyl] glycinate.

8.8 grams of ethyl-N-[4-carbethcxyphenyll glycinate is boiled three to four hours in 100 cc.

acidifying pure NE4-carboxyphenyll glycine separates.

A mixture of 3.85 grams 2,4,5-triamino-6-hydroxypyrimidine sulfate monohydrate and 3.66 grams barium chloride dihydrate in 70 cc. water was heated to 60 C. for minutes. After cooling to 40 C. 0.925 gram of N-(4-carboxyphenyl) glycine is added and the pH adjusted to 3-4. Keeping the mixture at 40 C. 3 cc. of a solution of 2,3-dibromopropionaldehyde in acetic acid is added simultaneously with a solution of 6.25 grams iodine and 12.5 grams potassium iodide in 40 cc. water and with 50% caustic to maintain pH 3-4. The crude 4-[N-(2-amino-4-hydroxypyrimido [4,5-bl pyrazyl-B-methyl)-N-carboxymethylaminol benzoic acid is. isolated with a filter aid. It shows antagonist activity against pteroylglutamic acid.

Example XIII A slurry of 26 grams 2,4,5,6-tetraamin0pyrimidine dihydrate sulfate, 24 grams barium chloride dihydrate, and grams of p-methylaminobenzoic acid in 700 cc. Water is heated at 80 C. for five minutes, adjusted to pH 3, and treated with 59 grams 1,1,3-tribromoacetone. The mixture is heated at 80 C. for one hour, the pH being kept at 3 by addition of 50% caustic solution. After cooling to 10 C. the crude 4-[N-(2,4-diaminopyrimido [4,5-b] pyrazyl-G-methyl)-N-methylamino] benzoic acid is filtered, washed and dried.

A slurry of 30 grams of the crude material in 1 liter of water containing six grams lime is heated 40 minutes at 60 C. and filtered at this temperature. The cake is washed with water and hydrochloric acid added to the filtrate to adjust to pH 3.02. After cooling in the icebox overnight the precipitate is filtered off and slurried in 750 00. water containing sodium hydroxide to give pH 11.0-11.6 at 80 C. When the material is all in solution, the mixture is adjusted to pH 7 while cooling to C. After filtering, the pH is adjusted to 4-5 with hydrochloric acid, and the precipitated material filtered off. The cake is slurried in 500 cc. water and treated with magnesium oxide to obtain pH 8.9-9.3 at 80 C. 0.5 gram Darco is added, and the heating at 80 C. continued for 15 minutes more. After filtering, the filtrate is adjusted to pH 4-5 with dilute hydrochloric acid and cooled several hours at 10 C. The yellow-orange crystalline material which is isolated by filtration weighs about one gram.

Example XIV A slurry of 15.8 grams 2-sulfhydryl-4-hydroxy- 5,6-diaminopyrimidine and 15 grams p-methylaminobenzoic acid in I00 cc. water is heated at 40 C. and adjusted to pH 3-4. Over a 20 minute period are added simultaneously 21.6 grams dibromopropionaldehyde in 21.6 grams acetic acid, and 5 N sodium hydroxide to maintain pH 3-4. After stirring 10 minutes more and cooling to 20 C., the crude 4[N-(2-sulfhydryl-4-hydroxypyrimido [4,5-b] pyrazyl-G-methyl)-N-methylamino] benzoic acid is isolated by filtration.

0n diluting, cooling, and

Example XV 4- [N- (2,4-dihydroxypyrimido [4,5-bl pyrazyl- G-methyD-N-methylaminol benzoic acid is prepared as described above except that 14.2 grams 2,4-dihydroxy-5,6-diaminopyrimidine is used for the diaminopyrimidine.

Evample XVI 4 [N (2-methylpyrimido[4,5-b] pYrazyl-G- methyl)-N-methylaminol benzoic acid is prepared as described above except that 12.4 grams 2-methyl-5,6-diaminopyrimidine is used for the diaminopyrimidine.

Example XVII 4 [N-(4-methylpyrimido[4,5-bl pyrazyl-G methyl) -N-methylaminol benzoic acid is prepared as described above except that 12.4grams 4-methyl-5,6-diaminopyrimidine is used for the diaminopyrimidine.

- Example XVIII 4' [(pyrimido[4,5 bl pyrazyl-6-methyl)-N- methylaminol benzoic acid is prepared as described above except the 11.0 grams 4,5-diaminopyrimidine is used.

Example XIX A mixture of 25.7 grams 2,4,5-triamino-6-hydroxypyrimidine sulfate monohydrate, 24.4 grams barium chloride dihydrate, and 700 cc. water are heated to 60 C. for 10 minutes. After cooling to 40 C. 15 grams p-methylaminobenzoic acid is added and the mixture adjusted to pH 3-4. Simultaneously and at 40 C. solutions of 21.6 grams of 2,3-dibromopropionaldehyde in acetic acid and sodium hydroxide to maintain pH 3-4 are added. The mixture is cooled after the reaction is completed and the 4-[N-(2- amino 4 hydroxypyrimido[4,5-bl pyrazyl-6- methyl) -N-methylamino]benzoic acid is collected on the filter, washed with water and dried.

Example XX A slurry of 28 grams 2,4.5,6-tetraaminopyrimidirne dihydrate sulfate, 24 grams barium chloride dihydrate, and 32 grains disodium pmethylaminobenzoylglutamic acid in 700 cc. water is heated at C. for 10 minutes, cooled to 40 C. and adjusted to pH 3-4. Then over a 20 minute period are added simultaneously 21.6 grams dibromopropionaldehyde in 21.6 grams acetic acid, 12.5 grams iodine and 25 grams potassium iodide in cc. water, and 5 N sodium hydroxide to maintain pH 3-4. After stirring 10 minutes more and cooling to 20 C., the crude 4- [N (2,4 diaminopyrimido[4,5-b] pyrazyl-6- methyl) -N-methylaminol benzoylglutamic acid is isolated by filtration and is an antagonist to pteroylglutamic acid.

The crude is purified as in Example XIII.

Example XXI 4-[N-(4-methylpyrimido [4,5-b] pyrazyl-G- methyl) -N-methylaminol benzoylglutamic acid is prepared as described above except that 12.4

' grams 4-methyl-5,6-diaminopyrimidine is used for the diaminopyrimidine.

We claim: 1. Compounds having the general formula CHzN N RI Xi in which X and Y are members of the group congaiaasva sisting: of hydrogen; hydroxy, sulfhydryh alkyl, halop'and"aminoradicalsgR is a-radical of the group consisting ofualkyl' and substitutedalkyl radicals, andR/ is'a' monocyclic aromatic radical of the benzene series'ii.

2iCo'mpounds1 having the general formula 1 N "R' I OcoNno-tro'oonomomooon in which X and Y are members of the group consisting of hydrogen, hydroxy, sulfhydryl, alkyl, halo, and amino radicals and R is a radical of the group consisting of alkyl and substituted alkyl radicals.

3. Compounds having the general formula I N /CH CHgN Ooomronooonomomooon L in which X and Y are members of the group consisting of hydrogen, hydroxy, sulfhydryl, alkyl, halo, and amino radicals.

4. Compounds having the general formula N N CHQN in which X and Y are members of the group consisting of hydrogen, hydroxy, sulfhydryl, alkyl, halo, and amino radicals, R is a radical of the group consisting of alkyl and substituted alkyl radicals, and NHR" is the radical of an amino acid.

5. Compounds having the general formula N CH2N/ A I NH N \N in which R is a radical of the group consisting of alkyl and substituted alkyl radicals, and R is a monocyclic aromatic radical of the benzene series.

6. Compounds having the general formula '7. Compounds having the general formula onN l l NH N N 8. A method of preparing compounds having the general formula N h CHiN Xi I in which X an'dY are members of the group consisting of hydrogen, hydroxy, sulfhydryl, alkyl, halo, and amino radicals, R is a radical of the group consisting of alkyl and substituted alkyl radicals, and R, is a monocyclic aromatic radical of the benzene series, which comprises the steps of mixing together under reactive conditions a 2,6-disubstituted-4,5 diaminopyrimidine, an alpha, beta-dihalopropionaldehyde, and a secondary amine, andafter-reaction thereof recovering the said product.

9.,A method of pr eparing compounds having the general formula in which X and Y are members of the group consisting of hydrogen, hydroxy, sulfhydryl, alkyl, halo, and amino radicals, R. is a radical of the group consisting of alkyl and substituted alkyl radicals, and. R is a monocyclic aromatic radical of the benzene series, which comprises the steps of mixing together under reactive conditions a 2,6-disubstituted-4,5-diaminopyrimidine, an alpha, beta-dichloropropionaldehyde, and a secondary amine, and after reaction thereof recovering the said product.

10. A method of preparing compounds having the general formula N N GHnN RI NHr-k in which R is a radical of the group consisting of alkyl and substituted alkyl radicals, and R. is a monocyclic aromatic radical of the benzene series, which comprises mixing together under reactive conditions 2,4,5,S-tetraaminopyrimidine, a dihalopropionaldehyde, and a secondary amine and after reaction thereof recovering the said product.

13. A method of preparing compounds having the general formula 011:) N N CHn-N in which NHR" is the radical of an amino acid, and after reaction thereof recovering the said product, which comprises mixing together under 15. A process which comprises mixing together reactive conditions 2,4,5,6-tetraaminopyrimidine, under reactive conditions 2,4,5,6-tetraaminohaving the formula a dihalopropionaldehyde, and a secondary amine pyrimidine, a dihalopropionaldehyde, and

- p-methylaminobenzoylglutamic acid. 5 JAMES M. SMITH, JR.

' DONNA B. COSULICH.

HN/ v 0 REFERENCES CITED ,inwhich NHR" is the radicl of an amino acid, The following references ar record in the and after reaction thereof recovering the said m file of this Patent:

Product I 1 Angier et aL, Science 103, No. 2683 667-669 14. Compounds having the general formula 194 GHN 000E Gammon NHLN N (kHz OOH 

1. COMPOUNDS HAVING THE GENERAL FORMULA
 8. A METHOD OF PREPARING COMPOUNDS HAVING THE GENERAL FORMULA 